The introduction of HIV antiretroviral medication (ARVs) in Africa have resulted in substantial reductions in morbidity and mortality, and in related social benefits. However, ARV programs have encountered many challenges, some of which are similar to those observed in North America (such as behavioral disinhibition), and some of which differ (including the availability of a limited range of ARV regimens, widespread use of nevirapine for prevention of mother-to-child HIV transmission, and the presence of non-B HIV subtypes). This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study in Uganda, the impact of ARVs on HIV transmission among HIV discordant couples, the impact of immunologic monitoring and potential delays in detecting virologic failure on genotypic antiretroviral resistance, and the role of suppressive acyclovir therapy in HSV-2/HIV-1 co-infected individuals on HIV-1 disease progression and time to initiation of ARVs. Because of Rakai's clinical, laboratory and community-based infrastructure, and the wealth of information available on the general population prior to the initiation of ARVs, the Rakai Program provides a unique opportunity to examine a broad range of ARV effects in a rural African setting. Referred to as the International Center for Excellence in Research (ICER), we are currently evaluating the impact of ARVs on HIV incidence among HIV discordant couples. 250 HIV-1 discordant couples were followed between 2004-2009. During this period 32 HIV-1-positive partners were initiated on ARVs since they met immunologic criteria for initiation of therapy. 42 HIV-1 transmissions occurred over 459.4 person-years prior to ARV initiation with an incidence of 9.2/100 pyo (95% CI, 6.59-12.36). In the 32 couples in which HIV-1 index partners started ARVs, no HIV-1 transmissions occurred during 53.6 person-years of follow-up while on ARVs. Couples reported more consistent condom use with marital or any partners during the periods while the positive partner was on ARVs and there was no significant difference in the number of sexual partners in the past 12 months or other risk behaviors. Data from this study as well as others now clearly demonstrate that antiretroviral therapy reduces the risk of HIV transmission among HIV-1 discordant. One concern with increased use of ARVs in sub-Saharan Africa is the extent by which viral resistance will develop over time among the non-clade B HIV-1-infected individuals. We genotyped 16 HIV-1-infected individuals with virologic failure, who were enrolled in an open-label, randomized clinical trial of short-cycle treatment interruption. All patients receiving efavirenz-containing HAART had >1 efavirenz resistance mutation develop during follow-up. The majority (86%) developed lamivudine resistance during follow-up but no thymidine analog mutations (TAMs) developed during the median duration of virologic failure of one year. In summary, genotype resistance to both efavirenz and lamivudine developed early during the course of treatment after virologic failure. TAMs did not emerge early despite moderate exposure to thymidine analogs thereby preserving the use of these alternative anti-retroviral drugs. Community health workers are essential in the provision of care but there was limited trial-based evidence on the effectiveness of community health workers in improving AIDS care outcomes. We conducted a clustered randomized trial to assess the effect of community-based peer health workers on AIDS care of adults in Rakai, Uganda. Fifteen HIV/AIDS clinics were randomized to: receive peer health worker (PHW) intervention or standard of care. Primary outcomes were adherence and cumulative risk of virologic failure;secondary outcomes were virologic failure. From May 2006 to July 2008 1,336 patients were followed of whom a third were already on ART at the start of the study. No significant differences were found in lack of adherence, cumulative risk of virologic failure, or in short-term virologic outcomes. However, virologic failure rates at 96 weeks on ART were significantly lower in the intervention arm compared to the control arm (RR 0.50, 95% CI, 0.31-0.81). From these data it is apparent that community-based peer health workers could be utilized in the provision of ARVs in a rural African community with effective ARV associated clinical outcomes. The etiology of fever among HIV-infected individuals has not been studied in detail in sub-Saharan Africa. We undertook a collaborative study to examine the etiology of severe sepsis in two Ugandan hospitals among a predominantly HIV-infected population. 382 patients met our enrollment criteria for severe sepsis. 85% of the patients were HIV infected with median CD4 T-cells of 52 cells/mm3. Overall mortality was 43% with 32% in-hospital mortality and 22% post-discharge mortality. Significant predictors of in-hospital mortality included admission Glasgow-Coma scale, Karnofsky performance scale, tachypnea leukocytosis, and thrombocytopenia. Discharge KPS and early fluid resuscitation were significant predictors of post-discharge mortality. Among HIV-infected patients CD4 count was a significant predictor of post-discharge mortality. 52 different empiric anti-bacterial regimens were used during the study. Bacteremic patients were more likely to die in hospital than non-bacteremic patients and patients with Mycobacterium tuberculosis bacteremia 25/249 had higher in-hospital mortality and lower median CD4 counts (p = 0.001) than patients without M. tuberculosis bacteremia. From this study it is apparent that patients presenting with severe sepsis in Uganda had late-stage HIV infection and very high mortality rates. Bacteremia especially from M. tuberculosis was associated with increased in-hospital mortality. Most clinical predictors of in-hospital mortality were easily measurable and can be used for triaging patients in resource-constrained settings. In the evaluation of these individuals, we also conducted a study to determine the utility of a point-of-care malaria rapid diagnostic assay to exclude malaria as a cause of fever in HIV-positive individuals in Uganda. 246 samples were analyzed including 14 (5.7) which were thick smear-positive for P. falciparum malaria. The sensitivity of the Binax-M compared with thick smears for malaria were 85.7%, specificity 97.8%, positive and negative predictive values were 70.6% and 99.1%, respectively. The rapid diagnostic test accurately ruled malaria in or out at the point-of-care facilitating appropriate clinical management and averting unnecessary anti-malarial therapy. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. We have previously published data from Rakai showing that individuals who are HSV-2 seropositive at the time of HIV-1 seroconversion had higher HIV viral loads at 5 and 15 months post-seroconversion. The potential of acyclovir to slow HIV-1 disease progression was recently shown in the partners in prevention study that observed a 17% reduction in progression to CD4<250 among HIV infected individuals treated with acyclovir 400mg twice daily. We are currently conducting a double blind placebo controlled trial to assess the benefits of acyclovir prophylaxis among HIV-1 infected individuals dually infected with HSV-2 who are not on ART to examine the impact of HSV-2 suppression on HIV-1 disease progression.